PROJECT SUMMARY/ABSTRACT Severe to moderate traumatic brain injury (smTBI) annually afflicts many hundreds of thousands of Americans producing chronic cognitive disabilities that lack effective treatments. The present proposal will develop a critical first-in-man early clinical feasibility study to support a next generation device to provide central thalamic deep brain stimulation (CT-DBS). CT-DBS is proposed as a therapy for the survivors of smTBI who recover to independent functional levels but remain significantly limited in their activities by chronic cognitive impairment (difficulties with sustained attentional effort, working memory, processing speed and fatigue). Stakeholders, including patients identifying their cognitive difficulties as matched to the functions proposed to be supported by CT-DBS, have shown support for this approach and willingness to consider participation after having the concepts and risks of this approach presented to them. The working hypothesis for the present study is that the pattern of cognitive deficits seen after smTBI takes origin in a broad reduction of neuronal connections and cell loss produced by smTBI that will on average produce disproportionate down-regulation of frontostriatal systems and deafferentation of the central thalamus (which collectively support the range of executive cognitive functions typically impaired in smTBI), and that CT-DBS can activate these systems sufficiently to provide effective functional improvements. Preliminary studies including evidence of CT-DBS facilitation of cognitive function in a different, more severely brain-injured population of patients with traumatic brain injuries as well as pre-clinical behavioral, electrophysiological, and computational modeling studies in intact non-human primates (NHP) support the hypothesis and the approach. The present study will use bilateral placement of a research single- electrode system with sensing and recording capabilities to aid the electrophysiological mapping of the central thalamus. Our supporting data demonstrate that behavioral facilitation can be achieved with a single electrode system in both the human and NHP. In NHP studies we have found that a more reliable and robust therapeutic response can be achieved through the use of a multiple electrode system capable of targeted delivery of electric fields across a specific fiber tract in the central thalamus. Here we will obtain and analyze neuroimaging, computational modeling, behavioral, and electrophysiological data from human subjects to advance the development of a next-generation system that may allow more flexibility and reliability of for the application of CT-DBS in patients with traumatic brain injuries. These studies will be carried out by an investigative team with multiple, long-standing collaborations aimed at the development of CT-DBS technologies and treatment of cognitive impairment following TBI; the team spans expertise in clinical trials, neurology, neurosurgery, neurophysiology, neurorehabilitation, neuropsychology, radiology, and computational modeling. The early feasibility study proposed has been through a presubmission review for an Investigational Device Exemption with the Food and Drug Administration.